We have previously demonstrated that therapy with cyclophosphamide was successful as a treatment for Wegener's granulomatosis (WG); however, drug toxicity has limited its use in certain patients. We have therefore evaluated the safety and efficacy of methotrexate (MTX) as an alternative therapy for WG. Forty-two patients who did not have immediately life-threatening disease were studied. Weekly administration of MTX and prednisone resulted in remission of disease in 33/42 patients (79%). Nineteen of the 34 patients achieving remission experienced a relapse of disease. The estimated median time to relapse for all patients achieving remission was 29 months. Eighty percent of these relapses occurred in patients who had discontinued MTX or had reduced their dose to 15 mg/week or less. Long term follow-up of this patient cohort showed that of the 20 patients with glomerulonephritis, only 2 had any deterioration in renal function after treatment with MTX. Thus, MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. Based on these results, we have initiated a phase II trial to assess the comparative efficacy of using MTX versus mycophenolate mofetil for maintaining remission that has been induced by cyclophosphamide and glucocorticoids in patients with WG and related vasculitides. We are also investigating the potential for MTX to be used as maintenance therapy in patients in whom cyclophosphamide has induced a disease remission. In this protocol patients receive glucocorticoid plus cyclophosphamide therapy until remission of disease is achieved; cyclophosphamide is then switched to MTX for maintenance of remission. By using this approach, we hope to combine the efficacy of cyclophosphamide with the more favorable toxicity profile of MTX. Preliminary data on the first 31 patients entered into this study indicate that this regimen is effective and safe. Disease remission was achieved in all 31 patients with a median time to remission of 3 months (range 1-10 months). The median duration of follow up for this group is 21 months and only 5 (16%) of these 31 patients have experienced a disease relapse. Two patients were withdrawn from the study for drug-related toxicity (both developed MTX-pneumonitis). These preliminary results suggest that this cyclophosphamide /MTX regimen is highly effective and may represent a less toxic alternative to the standard CP regimen for patients with severe disease.In studies of disease pathogenesis we have found that peripheral blood lymphocytes from patients with active WG produce 10 to 20-fold higher levels of interferon-gamma compared with peripheral blood lymphocytes from normal controls. Increased production of tumor necrosis factor (TNF) by CD4 T lymphocytes and IL-12 by purified monocytes were also noted, but production of IL-4, IL-5, and IL-10 was not increased. The addition of recombinant IL-10 to cell cultures suppressed the overproduction of interferon-gamma by WG T cells in a dose-dependent manner. Based on thesefindings, we have initiated a therapeutic trial of the anti-inflammatory cytokine IL-10 in patients with active WG. We will also initiated a phase I/II trial to assess the safety, efficacy, and immunologic effects of a recombinant fusion protein that contains the extracellular portion of the p75 TNF receptor linked to the Fc portion of human IgG1 (TNFR:Fc). We are seeking to examine whether TNFR:Fc is able to reduce the need for glucocorticoid treatment and lower relapse rates in patients with WG.